Adult Height after Ketoconazole Treatment in Patients with Familial Male-Limited Precocious Puberty
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《临床内分泌与代谢杂志》
Abstract
Familial male-limited precocious puberty is a rare cause of precocious puberty due to activating mutations of the LH receptor, leading to early onset virilization and short stature. Two therapeutic approaches have been proposed: the P450 cytochrome inhibitor ketoconazole or combined treatment with spironolactone and testolactone. Results on adult heights have not been reported to date after these two treatments, and in this study we present results from five patients treated with ketoconazole at a median dose of 16.2 mg/kg·d for a median of 6.2 yr. Adult height was 173 cm (median; interquartile range, 14), similar to target height (175 cm; interquartile range, 9) and significantly higher than pretreatment predicted height (165 cm; interquartile range, 12; P < 0.01). During treatment, 39 of 58 (68%) testosterone measurements were less than 0.5 ng/ml (1.7 nmol/liter), nine of 58 (15%) were between 0.5 and 1 ng/ml (3.5 nmol/liter), and 10 of 58 (17%) were above 1 ng/ml. We observed a physiological increase in GnRH-stimulated LH levels after the age of 10 yr, and none of the patients had early activation of the gonadotropic axis. Liver tolerance was excellent, and only one patient had a transient and modest increase in serum transaminases. We conclude that ketoconazole is an efficient and well tolerated long-term treatment of familial male-limited precocious puberty that should be proposed as a first line therapy.
Introduction
FAMILIAL MALE-LIMITED precocious puberty (FMPP) is due to gonadotropin-independent isosexual precocious secretion of testosterone by Leydig cells resulting from activating mutations of the LH receptor (1, 2). Affected males usually begin pubertal development by 1–4 yr of age, with rapid growth, growth plate maturation, and progressive virilization. If untreated, FMPP can result in behavioral disturbance, premature epiphyseal fusion, and adult short stature (1, 3, 4).
Two approaches have been proposed for the treatment of FMPP: ketoconazole, a P450 cytochrome inhibitor, which inhibits adrenal and testicular androgen biosynthesis (5, 6, 7), or the combination of an antiandrogen to antagonize androgen action at the receptor level and an aromatase inhibitor to block the conversion of androgens to estrogens (8, 9, 10). In both cases, secondary activation of the gonadotropic axis can occur, and GnRH agonists may be added (7, 10). The major adverse effect of ketoconazole is the potentially severe hepatotoxicity (11, 12, 13). The combination of antiandrogen and aromatase inhibitor can pose compliance problems with the older aromatase inhibitors, and flutamide can cause hepatotoxicity. In addition, this drug regimen has no effect on the serum testosterone level, and efficacy must be assessed indirectly by monitoring growth, bone maturation, virilization, and sexual behavior (10, 14).
In this study we present the long-term results in five patients with FMPP treated with ketoconazole for 5–10 yr and followed to adult height.
Patients and Methods
Patients
All five contemporary patients with FMPP followed in our center were included in the study. Their characteristics are presented in Tables 1 and 2. All of them had a family history of FMPP and previously identified activating mutation in the LH receptor: M398T in three (15, 16) and I542L in two (17). The mutation was transmitted by the father of patient 1 and by the mothers of patients 2–4 (patients 2 and 3 and patients 4 and 5 are siblings). Target height calculation is probably underestimated in patient 1, whose affected father reported pubertal onset around 10 yr, is 169 cm tall, and has an unaffected brother of 174 cm. The great grandfather of patient 1 was also probably affected and was 160 cm tall.
Treatment
Ketoconazole (Nizoral, Janssen Pharmaceutica, Titusville, NJ) was given as 200-mg tablets, at the median [interquartile range (IQR)] initial dose of 19.5 ([4] range, 13.8–24) mg/kg·d. Treatment was later adjusted according to testosterone levels, with a maximal dose of 700 mg/d corresponding to 23 ([3] range, 19.8–26) mg/kg·d. In general, daily ketoconazole dose was increased by 100 mg if the testosterone level was above 0.5 ng/ml. The median dose overall was 16.2 [6.2] mg/kg·d. The median duration of treatment was 6.2 ([4] range, 5.5–10.4) yr. Families were instructed on the risk of glucocorticoid deficiency or liver damage. Liver enzymes and plasma cortisol and ACTH levels were carefully monitored every 2 months during the first 6 months of treatment and biyearly or yearly thereafter.
Methods
We used Sempé normative data for height, weight, and growth velocity at each visit (18). Bone age was determined by the method of Greulich and Pyle (19), whereas predicted height was determined by the Bailey-Pinneau method (20). Adult height was considered attained if growth velocity was 1 cm/yr or less and if bone age was at least 16 yr (98% of adult height) (20). Serum gonadotropins, testosterone, cortisol, and ACTH were measured as previously described (21). Patients and families were informed of the investigative nature of the treatment and gave their informed consent according to the rules of our local ethical committee.
Statistical analysis
Data are expressed as the median [IQR]. Changes with treatment were evaluated by ANOVA for repeated measures. P < 0.05 was considered significant. Statistical tests were performed with the SAS software package (SAS Institute, Inc., Cary, NC).
Results
Characteristics of FMPP patients
Age at onset of symptoms varied between 2.3 and 6 yr, and age at initiation of ketoconazole varied between 3.6 and 6 yr. Patients 3 and 5 were detected by familial screening. All patients had an accelerated growth velocity (range of SDS, 3.8–7.8) with different degrees of pubarche and increased testicular volume (range, 7–11 ml; Table 1). All patients had evidence of gonadotropin-independent testosterone secretion (Table 1). Patient 1 had been transiently treated with a GnRH agonist without any effect on testosterone level.
Growth velocity, bone age, and adult height
Growth velocity decreased from 12 [2.8] cm/yr before treatment to 6 [3.5] cm/yr during the first year of treatment, and to 4.6 [2.1] cm/yr during the second year of treatment. Growth velocity remained stable at later points during treatment. Growth velocity SDS decreased from 5.8 [2.8] before treatment to 0 [2.3] during the first year of treatment, and remained stable thereafter. Bone age was very significantly advanced before treatment, with the exception of patient 5. The difference between bone and chronological age progressively decreased from the second year of treatment on (Fig. 1). The median adult height was –0.3 [2.3], and all patients were within the normal range (–1.7 to +1.1 SDS). Adult height was significantly increased compared with pretreatment predicted height (173 [14] cm vs. 165 [12] cm; P < 0.01) and was similar to target height (175 cm; [9]; Table 2).
Clinical and endocrine evolution
During treatment, testicular volume and pubic hair stage were stable in all patients. Testosterone level was in the pubertal range before treatment (5.6 [3.4] ng/ml; 19.6 [12.2] nmol/liter), decreased during the first year of ketoconazole treatment to 0.2 [0.5] ng/ml (0.7 [1.7] nmol/liter), and remained low during treatment (P < 0.01; Fig. 2). During treatment, a total of 58 testosterone measurements were performed, of which 39 (68%) were less than 0.5 ng/ml (1.7 nmol/liter), nine (15%) were between 0.5–1 ng/ml (3.5 nmol/liter), and 10 (17%) were above 1 ng/ml. Most of the elevated values were in older children, in particular before initiation of GnRH agonist treatment in patient 4. After ketoconazole was interrupted, testosterone levels increased rapidly to 4 [0.6] ng/ml (14 [2.1] nmol/liter).
All patients had a blunted LH response to GnRH before treatment (0.5 [0.8] IU/liter). During treatment, approximately before the age of 10 yr, peak LH values tended to remain in the prepubertal range (we use 5–7 IU/liter as a threshold for gonadotropic axis activation) (22), and none of our patients had clear precocious activation of the gonadotropic axis (Fig. 3). Strikingly, in the four patients who were regularly tested, GnRH-stimulated peak LH increased at approximately 11–12 yr of age. Patient 4 had an LH peak of 7.9 IU/liter and accelerated bone age maturation at 11.4 yr and was the only patient treated with a GnRH agonist until the age of 13.7 yr. After ketoconazole was interrupted, the GnRH-stimulated LH peak strikingly decreased in the three patients tested, whereas the plasma testosterone level increased, indicating that testosterone production had become LH independent again.
Tolerance
Liver enzymes increased in patient 3 after 15 months of treatment with an aspartate aminotransferase level of 69 IU/liter (2 times normal values) and an alanine aminotransferase level of 102 IU/liter (2 times normal values), without clinical symptoms. Treatment was maintained, and liver enzymes normalized within 6 months. Repeated measurements of liver function tests were normal in the other four patients.
The plasma ACTH level initially increased to 347 pg/ml in patient 2, with plasma cortisol within normal range (21 μg/dl at 0800 h). The parents were instructed to give hydrocortisone in case of stress, and plasma ACTH levels decreased to 14 pg/ml within 6 months. All other patients had normal ACTH and cortisol levels during the study.
Discussion
This is, to our knowledge, the first report of a series of FMPP patients treated with ketoconazole until reaching adult height. The treatment was well tolerated, efficient at suppressing testosterone production over the long term, and resulted in normal adult height.
The adult heights of our patients were within normal values and target height range. Adult heights exceeded pretreatment predicted height by 5–13 cm. Patients 2 and 3 had an adult height of 165 cm (–1.7 SD). They had similarly suppressed T values than other patients, but were treated later (6 yr), and their height might have been influenced by parental height (father, 183 cm; mother, 155 cm). The main weakness of our study is the small number of patients, although FMPP is rare, and extended follow-up is difficult to achieve. In addition, we had to rely on the comparison with predicted height. However, adult height in untreated FMPP patients is notoriously low, averaging 159 ± 8 cm in a recent literature review (23). A placebo-controlled trial or comparison with other approaches was not considered feasible, given the small number of patients. Few data on long-term results of FMPP treatments are available in the literature. With ketoconazole, Bertelloni et al. (23) reported one treated patient with a low adult height of –2.2 SDS after a 3-yr treatment, and Holland (24) reported a patient with an adult height of 154 cm after a 1.5-yr treatment. Six years of treatment with both spironolactone and testolactone led to normalization of growth velocity, a decrease in the rate of bone maturation, and an increase in predicted adult height, but adult height data are not available (10). This combination is well tolerated, but monitoring of the treatment is indirect, whereas, serum testosterone is useful to monitor control during ketoconazole therapy and was less than 0.5 ng/ml in 68% of the measurements in our patients.
The acceleration of central gonadotropin maturation is well described in patients with peripheral causes of precocious puberty (25). During ketoconazole treatment, this phenomenon was reported in seven of 16 patients (23, 24), but was not noted in our five patients. With the spironolactone/testolactone therapy, all 10 patients had advanced central puberty and were treated with GnRH agonists as well (10). This apparent difference might be due at least in part to the effect of testolactone in suppressing estrogen levels and the negative feedback of estrogen on LH secretion (26). However, the respective doses and potencies of the agents used might be involved, and we cannot derive mechanistic conclusions from these clinical observations given the complex interplay of gonadal and testicular androgens, their aromatized derivatives, and pubertal maturation of the gonadotropic axis (27).
FMPP is a genetically heterogeneous disorder caused by diverse activating mutations of the LH receptor that might respond variably to ketoconazole treatment. For example, the strongly activating D578Y mutation is associated with an early and severe testotoxicosis phenotype and resistance to ketoconazole treatment (17, 28, 29). The M398T mutation is reported to have incomplete penetrance (15). Therefore, caution should be used in generalizing our findings, which might not apply to patients with all LH receptor mutations.
The main side-effect of ketoconazole, one of considerable concern, is hepatic injury. Idiosyncrasy is the presumed mechanism, although an immunoallergic mechanism has also been discussed (30). The prevalence of mild, asymptomatic, reversible elevation of serum transaminase levels in adults receiving an average of 200 mg ketoconazole/d is 5–17% (12, 30), with hepatitis developing in 2.9% (30). The main risk factor identified in the occurrence of hepatitis is older age (11, 12, 30); in patients with asymptomatic liver injury, usually the abnormal biochemical changes gradually return to normal despite continuing treatment (30). Severe liver damage is rare (31), and death attributable to ketoconazole occurred in a patient who continued treatment despite severe liver damage (32). In children with FMPP, one case of severe liver damage has been reported in a patient receiving a high dose (1200 mg/d) for 1 yr, with reversal on continuation of treatment at a lower dose (13). Serum transaminase levels increased transiently in one of the two patients reported by Bertelloni et al. (23), and hepatic damage was not detected in the patients reported by Holland (24). In our patients, ketoconazole hepatotoxicity was not a problem; only one of them had mild, transient, asymptomatic elevation of serum transaminases. Current recommendations for screening for risk of liver damage during ketoconazole treatments include the regular measurement of serum transaminases and discontinuation only if symptoms of hepatitis and/or hyperbilirubinemia occur (30). However, some reports (33) recommend discontinuation of ketoconazole if serum transaminases increase more than 3-fold above the upper limit of normal values; we recommend this approach.
In conclusion, in our patients with FMPP, ketoconazole was well tolerated and effective in suppressing both pubertal symptoms and increasing adult height significantly over that predicted before treatment. We suggest that ketoconazole is useful for initial treatment of FMPP; monitoring of testosterone levels demonstrates its efficacy within the first 3–6 months. In a patient who responds poorly, caution should be used in increasing the ketoconazole dosage, because it increases the risk of liver damage. A second treatment option, such as the combined use of an antiandrogen and an aromatase inhibitor, should then be considered.
Acknowledgments
We thank Andrew Shenker for performing genetic analysis in our patients.
Footnotes
First Published Online November 2, 2004
Abbreviations: FMPP, Familial male-limited precocious puberty; IQR, interquartile range; SDS, SD score.
Received July 21, 2004.
Accepted October 18, 2004.
References
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Familial male-limited precocious puberty is a rare cause of precocious puberty due to activating mutations of the LH receptor, leading to early onset virilization and short stature. Two therapeutic approaches have been proposed: the P450 cytochrome inhibitor ketoconazole or combined treatment with spironolactone and testolactone. Results on adult heights have not been reported to date after these two treatments, and in this study we present results from five patients treated with ketoconazole at a median dose of 16.2 mg/kg·d for a median of 6.2 yr. Adult height was 173 cm (median; interquartile range, 14), similar to target height (175 cm; interquartile range, 9) and significantly higher than pretreatment predicted height (165 cm; interquartile range, 12; P < 0.01). During treatment, 39 of 58 (68%) testosterone measurements were less than 0.5 ng/ml (1.7 nmol/liter), nine of 58 (15%) were between 0.5 and 1 ng/ml (3.5 nmol/liter), and 10 of 58 (17%) were above 1 ng/ml. We observed a physiological increase in GnRH-stimulated LH levels after the age of 10 yr, and none of the patients had early activation of the gonadotropic axis. Liver tolerance was excellent, and only one patient had a transient and modest increase in serum transaminases. We conclude that ketoconazole is an efficient and well tolerated long-term treatment of familial male-limited precocious puberty that should be proposed as a first line therapy.
Introduction
FAMILIAL MALE-LIMITED precocious puberty (FMPP) is due to gonadotropin-independent isosexual precocious secretion of testosterone by Leydig cells resulting from activating mutations of the LH receptor (1, 2). Affected males usually begin pubertal development by 1–4 yr of age, with rapid growth, growth plate maturation, and progressive virilization. If untreated, FMPP can result in behavioral disturbance, premature epiphyseal fusion, and adult short stature (1, 3, 4).
Two approaches have been proposed for the treatment of FMPP: ketoconazole, a P450 cytochrome inhibitor, which inhibits adrenal and testicular androgen biosynthesis (5, 6, 7), or the combination of an antiandrogen to antagonize androgen action at the receptor level and an aromatase inhibitor to block the conversion of androgens to estrogens (8, 9, 10). In both cases, secondary activation of the gonadotropic axis can occur, and GnRH agonists may be added (7, 10). The major adverse effect of ketoconazole is the potentially severe hepatotoxicity (11, 12, 13). The combination of antiandrogen and aromatase inhibitor can pose compliance problems with the older aromatase inhibitors, and flutamide can cause hepatotoxicity. In addition, this drug regimen has no effect on the serum testosterone level, and efficacy must be assessed indirectly by monitoring growth, bone maturation, virilization, and sexual behavior (10, 14).
In this study we present the long-term results in five patients with FMPP treated with ketoconazole for 5–10 yr and followed to adult height.
Patients and Methods
Patients
All five contemporary patients with FMPP followed in our center were included in the study. Their characteristics are presented in Tables 1 and 2. All of them had a family history of FMPP and previously identified activating mutation in the LH receptor: M398T in three (15, 16) and I542L in two (17). The mutation was transmitted by the father of patient 1 and by the mothers of patients 2–4 (patients 2 and 3 and patients 4 and 5 are siblings). Target height calculation is probably underestimated in patient 1, whose affected father reported pubertal onset around 10 yr, is 169 cm tall, and has an unaffected brother of 174 cm. The great grandfather of patient 1 was also probably affected and was 160 cm tall.
Treatment
Ketoconazole (Nizoral, Janssen Pharmaceutica, Titusville, NJ) was given as 200-mg tablets, at the median [interquartile range (IQR)] initial dose of 19.5 ([4] range, 13.8–24) mg/kg·d. Treatment was later adjusted according to testosterone levels, with a maximal dose of 700 mg/d corresponding to 23 ([3] range, 19.8–26) mg/kg·d. In general, daily ketoconazole dose was increased by 100 mg if the testosterone level was above 0.5 ng/ml. The median dose overall was 16.2 [6.2] mg/kg·d. The median duration of treatment was 6.2 ([4] range, 5.5–10.4) yr. Families were instructed on the risk of glucocorticoid deficiency or liver damage. Liver enzymes and plasma cortisol and ACTH levels were carefully monitored every 2 months during the first 6 months of treatment and biyearly or yearly thereafter.
Methods
We used Sempé normative data for height, weight, and growth velocity at each visit (18). Bone age was determined by the method of Greulich and Pyle (19), whereas predicted height was determined by the Bailey-Pinneau method (20). Adult height was considered attained if growth velocity was 1 cm/yr or less and if bone age was at least 16 yr (98% of adult height) (20). Serum gonadotropins, testosterone, cortisol, and ACTH were measured as previously described (21). Patients and families were informed of the investigative nature of the treatment and gave their informed consent according to the rules of our local ethical committee.
Statistical analysis
Data are expressed as the median [IQR]. Changes with treatment were evaluated by ANOVA for repeated measures. P < 0.05 was considered significant. Statistical tests were performed with the SAS software package (SAS Institute, Inc., Cary, NC).
Results
Characteristics of FMPP patients
Age at onset of symptoms varied between 2.3 and 6 yr, and age at initiation of ketoconazole varied between 3.6 and 6 yr. Patients 3 and 5 were detected by familial screening. All patients had an accelerated growth velocity (range of SDS, 3.8–7.8) with different degrees of pubarche and increased testicular volume (range, 7–11 ml; Table 1). All patients had evidence of gonadotropin-independent testosterone secretion (Table 1). Patient 1 had been transiently treated with a GnRH agonist without any effect on testosterone level.
Growth velocity, bone age, and adult height
Growth velocity decreased from 12 [2.8] cm/yr before treatment to 6 [3.5] cm/yr during the first year of treatment, and to 4.6 [2.1] cm/yr during the second year of treatment. Growth velocity remained stable at later points during treatment. Growth velocity SDS decreased from 5.8 [2.8] before treatment to 0 [2.3] during the first year of treatment, and remained stable thereafter. Bone age was very significantly advanced before treatment, with the exception of patient 5. The difference between bone and chronological age progressively decreased from the second year of treatment on (Fig. 1). The median adult height was –0.3 [2.3], and all patients were within the normal range (–1.7 to +1.1 SDS). Adult height was significantly increased compared with pretreatment predicted height (173 [14] cm vs. 165 [12] cm; P < 0.01) and was similar to target height (175 cm; [9]; Table 2).
Clinical and endocrine evolution
During treatment, testicular volume and pubic hair stage were stable in all patients. Testosterone level was in the pubertal range before treatment (5.6 [3.4] ng/ml; 19.6 [12.2] nmol/liter), decreased during the first year of ketoconazole treatment to 0.2 [0.5] ng/ml (0.7 [1.7] nmol/liter), and remained low during treatment (P < 0.01; Fig. 2). During treatment, a total of 58 testosterone measurements were performed, of which 39 (68%) were less than 0.5 ng/ml (1.7 nmol/liter), nine (15%) were between 0.5–1 ng/ml (3.5 nmol/liter), and 10 (17%) were above 1 ng/ml. Most of the elevated values were in older children, in particular before initiation of GnRH agonist treatment in patient 4. After ketoconazole was interrupted, testosterone levels increased rapidly to 4 [0.6] ng/ml (14 [2.1] nmol/liter).
All patients had a blunted LH response to GnRH before treatment (0.5 [0.8] IU/liter). During treatment, approximately before the age of 10 yr, peak LH values tended to remain in the prepubertal range (we use 5–7 IU/liter as a threshold for gonadotropic axis activation) (22), and none of our patients had clear precocious activation of the gonadotropic axis (Fig. 3). Strikingly, in the four patients who were regularly tested, GnRH-stimulated peak LH increased at approximately 11–12 yr of age. Patient 4 had an LH peak of 7.9 IU/liter and accelerated bone age maturation at 11.4 yr and was the only patient treated with a GnRH agonist until the age of 13.7 yr. After ketoconazole was interrupted, the GnRH-stimulated LH peak strikingly decreased in the three patients tested, whereas the plasma testosterone level increased, indicating that testosterone production had become LH independent again.
Tolerance
Liver enzymes increased in patient 3 after 15 months of treatment with an aspartate aminotransferase level of 69 IU/liter (2 times normal values) and an alanine aminotransferase level of 102 IU/liter (2 times normal values), without clinical symptoms. Treatment was maintained, and liver enzymes normalized within 6 months. Repeated measurements of liver function tests were normal in the other four patients.
The plasma ACTH level initially increased to 347 pg/ml in patient 2, with plasma cortisol within normal range (21 μg/dl at 0800 h). The parents were instructed to give hydrocortisone in case of stress, and plasma ACTH levels decreased to 14 pg/ml within 6 months. All other patients had normal ACTH and cortisol levels during the study.
Discussion
This is, to our knowledge, the first report of a series of FMPP patients treated with ketoconazole until reaching adult height. The treatment was well tolerated, efficient at suppressing testosterone production over the long term, and resulted in normal adult height.
The adult heights of our patients were within normal values and target height range. Adult heights exceeded pretreatment predicted height by 5–13 cm. Patients 2 and 3 had an adult height of 165 cm (–1.7 SD). They had similarly suppressed T values than other patients, but were treated later (6 yr), and their height might have been influenced by parental height (father, 183 cm; mother, 155 cm). The main weakness of our study is the small number of patients, although FMPP is rare, and extended follow-up is difficult to achieve. In addition, we had to rely on the comparison with predicted height. However, adult height in untreated FMPP patients is notoriously low, averaging 159 ± 8 cm in a recent literature review (23). A placebo-controlled trial or comparison with other approaches was not considered feasible, given the small number of patients. Few data on long-term results of FMPP treatments are available in the literature. With ketoconazole, Bertelloni et al. (23) reported one treated patient with a low adult height of –2.2 SDS after a 3-yr treatment, and Holland (24) reported a patient with an adult height of 154 cm after a 1.5-yr treatment. Six years of treatment with both spironolactone and testolactone led to normalization of growth velocity, a decrease in the rate of bone maturation, and an increase in predicted adult height, but adult height data are not available (10). This combination is well tolerated, but monitoring of the treatment is indirect, whereas, serum testosterone is useful to monitor control during ketoconazole therapy and was less than 0.5 ng/ml in 68% of the measurements in our patients.
The acceleration of central gonadotropin maturation is well described in patients with peripheral causes of precocious puberty (25). During ketoconazole treatment, this phenomenon was reported in seven of 16 patients (23, 24), but was not noted in our five patients. With the spironolactone/testolactone therapy, all 10 patients had advanced central puberty and were treated with GnRH agonists as well (10). This apparent difference might be due at least in part to the effect of testolactone in suppressing estrogen levels and the negative feedback of estrogen on LH secretion (26). However, the respective doses and potencies of the agents used might be involved, and we cannot derive mechanistic conclusions from these clinical observations given the complex interplay of gonadal and testicular androgens, their aromatized derivatives, and pubertal maturation of the gonadotropic axis (27).
FMPP is a genetically heterogeneous disorder caused by diverse activating mutations of the LH receptor that might respond variably to ketoconazole treatment. For example, the strongly activating D578Y mutation is associated with an early and severe testotoxicosis phenotype and resistance to ketoconazole treatment (17, 28, 29). The M398T mutation is reported to have incomplete penetrance (15). Therefore, caution should be used in generalizing our findings, which might not apply to patients with all LH receptor mutations.
The main side-effect of ketoconazole, one of considerable concern, is hepatic injury. Idiosyncrasy is the presumed mechanism, although an immunoallergic mechanism has also been discussed (30). The prevalence of mild, asymptomatic, reversible elevation of serum transaminase levels in adults receiving an average of 200 mg ketoconazole/d is 5–17% (12, 30), with hepatitis developing in 2.9% (30). The main risk factor identified in the occurrence of hepatitis is older age (11, 12, 30); in patients with asymptomatic liver injury, usually the abnormal biochemical changes gradually return to normal despite continuing treatment (30). Severe liver damage is rare (31), and death attributable to ketoconazole occurred in a patient who continued treatment despite severe liver damage (32). In children with FMPP, one case of severe liver damage has been reported in a patient receiving a high dose (1200 mg/d) for 1 yr, with reversal on continuation of treatment at a lower dose (13). Serum transaminase levels increased transiently in one of the two patients reported by Bertelloni et al. (23), and hepatic damage was not detected in the patients reported by Holland (24). In our patients, ketoconazole hepatotoxicity was not a problem; only one of them had mild, transient, asymptomatic elevation of serum transaminases. Current recommendations for screening for risk of liver damage during ketoconazole treatments include the regular measurement of serum transaminases and discontinuation only if symptoms of hepatitis and/or hyperbilirubinemia occur (30). However, some reports (33) recommend discontinuation of ketoconazole if serum transaminases increase more than 3-fold above the upper limit of normal values; we recommend this approach.
In conclusion, in our patients with FMPP, ketoconazole was well tolerated and effective in suppressing both pubertal symptoms and increasing adult height significantly over that predicted before treatment. We suggest that ketoconazole is useful for initial treatment of FMPP; monitoring of testosterone levels demonstrates its efficacy within the first 3–6 months. In a patient who responds poorly, caution should be used in increasing the ketoconazole dosage, because it increases the risk of liver damage. A second treatment option, such as the combined use of an antiandrogen and an aromatase inhibitor, should then be considered.
Acknowledgments
We thank Andrew Shenker for performing genetic analysis in our patients.
Footnotes
First Published Online November 2, 2004
Abbreviations: FMPP, Familial male-limited precocious puberty; IQR, interquartile range; SDS, SD score.
Received July 21, 2004.
Accepted October 18, 2004.
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